Nine inherited neurodegenerative disorders, including Huntington's disease (HD), are caused by the expansion of a polyglutamine (polyQ) domain in their associated disease proteins. A common pathological feature of these diseases is selective neurodegeneration in distinct brain regions associated with each disease, despite the widespread expression of mutant proteins throughout the brain and body. Understanding the mechanism by which expanded polyQ-containing proteins mediate selective neurodegeneration is critical for developing effective therapeutic strategies to treat these polyQ diseases. In HD patients, the selective neurodegeneration occurs first to the medium spiny neurons, which account for >90% of neurons in the striatum. In HD mice that express full-length mutant huntingtin (htt), there is a preferential accumulation of mutant htt in the nuclei of medium spiny neurons in the striatum. Since mutant htt in the nucleus interacts with transcription factors and affects gene expression, this preferential nuclear accumulation is believed to account for the selective neurodegeneration in the striatum. Understanding the mechanism for this nuclear localization will not only help elucidate the pathogenesis of HD, but also other polyQ diseases that feature nuclear accumulation and inclusions of polyQ proteins. We hypothesize that the nuclear localization of mutant htt stems from multiple factors. First, the full- length mutant htt must be degraded to generate small N-terminal htt fragments that can passively enter the nucleus to affect gene transcription. Second, cell type-specific factors can regulate the nuclear localization of mutant htt. To test these hypotheses, we will compare the subcellular distribution of full-length and N- terminal mutant htt in HD knock-in mice that express mutant htt at the endogenous level. The relationship between the nuclear accumulation of N-terminal mutant htt and neurological phenotypes or changes in gene expression will be evaluated. We will also investigate the cell type-specific toxicity of N-terminal mutant htt via the Cre-loxP system. These studies aim to test whether N-terminal mutant htt, when expressed at the endogenous level, accumulates more rapidly in the nucleus and causes more severe phenotypes than full-length mutant htt. We will also examine whether striatal neurons have specific molecules or factors that regulate N-terminal phosphorylation of mutant htt to promote its nuclear accumulation. These studies will help us develop therapies that alter htt phosphorylation to reduce the nuclear accumulation of mutant htt and its associated neuropathology. PUBLIC HEALTH RELEVANCE: Huntington disease (HD) is the most common form of polyglutamine diseases that are featured by abnormal gene expression caused by mutant proteins in the nucleus. In this application, we will use genetic mouse models of HD to investigate the mechanism by which the HD protein accumulates in neuronal nucleus. Elucidating this mechanism will help find therapeutic intervention to reduce HD neuropathology.